New piperazine derivatives



United States NEW PIPERAZINE DERIVATIVES Henri Morren, Forest-Brussels, Belgium, assignor to UlllOll Chimique Belge, 5A., Brussels, Belgium, a corporationof Belgium,

No Drawing. Filed Jan. 14, 19:59, Ser. No, vsasss priority, application Belgium Jan. 21 19 58 6 Claims. (Cl. 260268) The present invention relates to new piperazine derivatives of the general formula wherein R is selected from the group consisting of a hydrogen atom and a methyl radical, R' is selected from the group consisting of alkyl, hydroxyalkyl and alkoxyalkyl radicals containing from 1 to 5 carbon atoms.

The invention relates also to the preparation of these compounds and their salts of mineral or organic acids.

These new piperazine derivatives are very active antitussic agents whose activity was absolutely unexpected. The activity of these compounds exceed the efiiect produced by codeine (activity=1) as shown below:

R(R=H) Intravenous Activity activity per os -CH2-C(CH2OH):4... CH2CH2CH2OH --CH2CHOHCH3 A solution of 0.1 mole of l-methylpiperazine and 0.1 mole phenacyl chloride in 200 ml. of acetone is heated under reflux for 3 hours. The reaction mixture is then cooled.

The filtered crystals are dissolved in 60 ml. boiling E6111: 0 i J P tent d Apr. 25, 195 1 ethanol. One filters on active charcoal and adds a slight excess of an alcoholic solution of hydrochloric acid. The dihydrochloride crystallizes. About 13 g. of l-phenacyl- 4-methylpiperazine dihydrochloride melting at 228 C. are obtained.

Example 2.-1-phenacyl-4-isopropylpiperazine mon'ohydrochloride A solution of 0.07 mole of l-isopropylpiperazine and 0.07 mole of phenacyl chloride in 150 ml. of acetone is heated under reflux for 2 hours. I

After cooling, the crystals are filtered and crystallized again in boiling ethanol. 9.5 g. of 1-phenacyl-4-isopropy1- piperazine monohydrochloride, melting at 178 C., are obtained.

Example 3.I-phenacyl-4-pr0pylpiperazine mor ohydrochloride N-CHr-CHr-CHs-HCI CHPCHZ This product, obtained by the method of Example 1, from l-propylpiperazine melts at C. ,It is crystal.- lized again in an ethanol-ether mixture.

Example 4.--1-ph enacyl-4- (Z-hydroxyethyl) -piperazine dihydrochloride This compound is prepared according to the method de: scribed in Example 1 from l-(2-hydroxyethyl)-piperazine and phenacyl chloride. Melting point: 240 C.

Example 5.1-phenacyl-4-[2-(2-hydroxyeth0xy)- ethyl]-piperazine dihydrochloride CHrCHfl A mixture of 0.5 mole of 1-[2-(2-hydroxyethoxy)- ethyl] -piperazine, 0.6 mole of triethylarnine and 0.5 mole of phenacyl chloride in 500 ml. of toluene is heated under reflux for 4 hours.

After cooling, the triethylamine hydrochloride is filtered. The organic solution is boiled ofi under vacuum. The residue, dissolved in boiling ethanol, is filtered on active charcoal. One adds to this solution a slight excess of an alcoholic solution of hydrochloric acid. After crystallization, 154 g. of 1-phenacyl-4-[2-(Z-hydroxyethoxy)-ethyl]-piperazine dihydrochloride, melting at 205 C., are obtained.

Example 6 -pIzenacyl-4-( 2,3-dihydr0xypropyl piperazine monohydrochlo ride N-CH -CHOH-CHzOHHCl CHz-CHz A solution of 2 moles of phenacyl chloride in 500 m1. of l-butanol is added slowly and with stirring to a hot solution of 2 moles of 1-(2,3-dihydroxypropyl)-piperazine in 1 liter of l-butanolJ The reaction mixture is heated under reflux for 5 hours.

After cooling, the crystals formed are filtered and crystallized again in 3.5 liters of boiling methanol.

The l-phenacyl 4 (2,3-dihydroxypropyl)-piperazine monohydrochloride, obtained in a yield of 76%, melts at A 4 I To a hot solution of 3 moles of piperazine in 1 liter of toluene is added with stirring a solution of 1 mole of phenacyl chloride in 250 ml: of toluene. This mixture is heated under reflux for 10 hours and thereafter al- 5 lowed to stand for 15 hours. The formed solid is filtered and the toluenic solution is washed twice with water. The toluenic solution is dried and the solvent is there after removed under vacuum. The residue is' dissolved in 500 ml. of ethanol.

The hot solution is poured in a hot solution of 2 moles of maleic acid in 900 ml. of ethanol. 7

After crystallization, 305 g. of V l-phenacyl-piperazine The following products are obtained according to the process oflthis example; v 1-phenacyl-4-(Z-hydroxypropyl)-piperazine i i V Melting point; 255 C. (with decomposition) l-phenacyl-4-(3-hydroxypropyl)-piperazine Melting point: 210-2ll C.

Example 7.-1- phenacyl-4-(2,2-dimethyl0l-3-hydr0xy- 10 pmpyD-piperazine OHPCH F d 1 t r m f 1 c H N 0 2c 0 H 1n lma Ca e O 6 ormu a 12 18 2 4 4 4, me ng C0 cHT N N CH' C-CH'OH at 160 C. (with decomposition), areobtained. e 1

CHaOH The chemical analysis gives the following results: An aqueous solution of sodium hydroxide is added to 1 9 Percent N 0.11 mole of l-phenacyl-piperazine dimaleate. The liber- Calculated 6A2 ated base is extracted three times with 100 ml. of benzene.

Found p 6.36

20 I claim: v

1. 1-phenacyl-4-(2-hydroxyethyl)-piperazine. 2. 1-phenacyl-4-(2-hydroxypropyl)-piperazine. 3. 1-phenacyl-4-( 3-hydroxypropyl -piperazine. 4.1-phenacyl-4-(2,3-dihydroxypropyl)-piperazine. 5. 1-phenacyl-4-(2,2-dimethylol 3 hydroxypropyD The benzenic extracting solutions are dried with potassium carbonate. i e l The organic solvent is boiled oil and the residue is dissolved in 100 ml. of l-butanol. To this solution is added a solution of 0.1 mole of pentaerythritol bromhydrin in 50 ml. of lbutanol. The reaction mixture is heated under reflux for 10 hours.

The reaction product is cooled and 300 ml. of anhypiperazine. r g drous ethyl ether is added. After vigorous stlrring, the 1 h 1- 4 2 (2 hydroxyethoxy) h l mixture is allowed to stand. The solution is decanted and filtered on bone charcoal. The solvent is removed plprerazme' under vacuum and the residue'is dissolved in boiling ethanol. After cooling, 1-phenacyl-4-(2,2-dimethylol-3- hydroxypropyl)-piperazine of the formula C I-1 N 0 is References Cited in the file of this patent UNITED STATES PATENTS obtained with a melting point of 129 C. Yield: 25%. 2,881,172 Weston et al. ...2 Apr. 7, 1959 The chemical analysis gives the following reiultsz N FOREIGN PATENTS V ercent Calculated 8.69 789,704 Great Britain Jan. 29, 1958 Found 8.62 OTHER REFERENCES The l-phenacyl-piperazine dimaleate used as starting I Harfenist: Jour. Amer. Chem. Soc., vol. 76, pages product is obtained as follows: 

1. 1-PHENACYL-4-(2-HYDROXYETHYL)-PIPERAZINE. 